Drug addiction and abuse is a global problem that produces a significant strain on healthcare systems and the lives of individuals and their families. Repeated exposure to drugs of abuse alters the function of the nervous system and produce states that encourage continued drug use. These alterations occur at multiple levels of the nervous system, including functional changes within the brain's reward circuit. One region of this system known to be important in mediating the rewarding aspects of drugs of abuse and many of the animal behavioral consequences of repeated drug exposure is the Nucleus Accumbens (NAc). Epigenetic changes are mediated in part by enzymes such as class IIa histone deacetylases (HDACs) that can produce long lasting experience-dependent changes in the level of gene transcription and thusly protein expression. Class IIa HDACs have been previously implicated in drug reward and associated behaviors mediated by the NAc. Understanding the role of HDACs' regulation in the control of drug related behavior could identify pathways that contribute to addiction. These mechanisms will be future targets for pharmacotherapies to treat addiction and improve abstinence. HDAC4 is a member of the Class IIa family previously implicated in drug-related behaviors via its transcriptional regulation activty in the NAc. Previous research has shown that over-expression of HDAC4 in the NAc can oppose cocaine's rewarding effects. When localized to the nucleus, Class IIa HDACs repress the transcription of a number of genes, including those known to be important for responses to psychostimulants. This activity is disrupted when Class IIa HDACs are translocated to the cytoplasm. The phosphorylation state of Class IIa HDACs governs their nucleo-cytoplasmic localization and cocaine has been shown to alter the phosphorylation and localization of the closely related HDAC5. It is still unknown how cocaine impacts HDAC4 phosphorylation and localization and what effect HDAC4 localization has on the rewarding effects of cocaine. This proposal will identify the effect of chronic or acute cocaine administration on the subcellular localization and phosphorylation state of HDAC4. Informed by these findings, mutant forms of HDAC4 that enhance specific localization patterns will be generated and characterized. These mutant forms will then be used, along with conditional knockout of HDAC4, to probe the role of HDAC4 expression and localization on cocaine reward. These experiments will address the gap in our knowledge of the regulation, localization, and role in reward of HDAC4. Understanding how HDAC4's localization is affected by cocaine and how it's activity affects cocaine reward is only the start in a series of promising studies into the role of this molecule in cocaine addiction